scholarly journals POT1 mutation spectrum in tumour types commonly diagnosed among POT1-associated hereditary cancer syndrome families

2020 ◽  
Vol 57 (10) ◽  
pp. 664-670 ◽  
Author(s):  
Erica Shen ◽  
Joanne Xiu ◽  
Giselle Y Lopez ◽  
Rex Bentley ◽  
Ali Jalali ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mutation Frequency ◽  
Genome Instability ◽  
Familial Cancer ◽  
Malignant Gliomas ◽  
Hereditary Cancer Syndrome ◽  
Cancer Syndrome ◽  
Telomere Elongation ◽  
Telomere Lengthening ◽  
Regulate Telomere Length

BackgroundThe shelterin complex is composed of six proteins that protect and regulate telomere length, including protection of telomeres 1 (POT1). Germline POT1 mutations are associated with an autosomal dominant familial cancer syndrome presenting with diverse malignancies, including glioma, angiosarcoma, colorectal cancer and melanoma. Although somatic POT1 mutations promote telomere elongation and genome instability in chronic lymphocytic leukaemia, the contribution of POT1 mutations to development of other sporadic cancers is largely unexplored.MethodsWe performed logistic regression, adjusted for tumour mutational burden, to identify associations between POT1 mutation frequency and tumour type in 62 368 tumours undergoing next-generation sequencing.ResultsA total of 1834 tumours harboured a non-benign mutation of POT1 (2.94%), of which 128 harboured a mutation previously reported to confer familial cancer risk in the setting of germline POT1 deficiency. Angiosarcoma was 11 times more likely than other tumours to harbour a POT1 mutation (p=1.4×10−20), and 65% of POT1-mutated angiosarcoma had >1 mutations in POT1. Malignant gliomas were 1.7 times less likely to harbour a POT1 mutation (p=1.2×10−3) than other tumour types. Colorectal cancer was 1.2 times less likely to harbour a POT1 mutation (p=0.012), while melanoma showed no differences in POT1 mutation frequency versus other tumours (p=0.67).ConclusionsThese results confirm a role for shelterin dysfunction in angiosarcoma development but suggest that gliomas arising in the context of germline POT1 deficiency activate a telomere-lengthening mechanism that is uncommon in gliomagenesis.

Epidemiology and Molecular Biology of Colorectal Cancer

2017 ◽  
Author(s):  
Tarik Sammour ◽  
Miguel A Rodriguez-Bigas
Keyword(s):  
Colorectal Cancer ◽  
Risk Factors ◽  
Familial Cancer ◽  
The United States ◽  
Diagnostic Techniques ◽  
Genetic Mutation ◽  
Cancer Syndrome ◽  
Key Words Colon Cancer ◽  
Serrated Carcinoma ◽  
Red Meats

Colorectal cancer (CRC) is the fourth most common cancer and the second most common cause of cancer-related death in the United States. Nonmodifiable risk factors include age, male sex, African-American ethnicity, and personal or family history of CRC or polyps (especially if these were diagnosed at a younger age), inflammatory bowel disease, or diabetes. Modifiable risk factors include poor physical activity; obesity; high consumption of red meats, processed meats, or alcohol; low total dietary intake of fiber, folate, fruits, or vegetables; and smoking tobacco. There have been several advances in diagnostic techniques, which, when combined with newly discovered genetic pathways, contribute to an expanding knowledge on which to base treatment. There are three known major molecular pathways of CRC carcinogenesis: the chromosomal instability pathway, the microsatellite instability pathway, and the serrated carcinoma pathway. Approximately 5% of all CRC cases will have a specific known genetic mutation associated with a well-characterized familial cancer syndrome with defined features. These syndromes are important to recognize distinctly as their identification facilitates surveillance and management with the aim of prevention, prophylaxis, and surgical cure. This review contains 2 figures, 3 tables and 50 references.  Key words: colon cancer, colorectal cancer, familial, familial adenomatous polyposis, Lynch syndrome, microsatellite, polyp, polyposis, rectal cancer, serrated

Epidemiology and Molecular Biology of Colorectal Cancer

2017 ◽  
Author(s):  
Tarik Sammour ◽  
Miguel A Rodriguez-Bigas
Keyword(s):  
Colorectal Cancer ◽  
Risk Factors ◽  
Familial Cancer ◽  
The United States ◽  
Diagnostic Techniques ◽  
Genetic Mutation ◽  
Cancer Syndrome ◽  
Key Words Colon Cancer ◽  
Serrated Carcinoma ◽  
Red Meats

Colorectal cancer (CRC) is the fourth most common cancer and the second most common cause of cancer-related death in the United States. Nonmodifiable risk factors include age, male sex, African-American ethnicity, and personal or family history of CRC or polyps (especially if these were diagnosed at a younger age), inflammatory bowel disease, or diabetes. Modifiable risk factors include poor physical activity; obesity; high consumption of red meats, processed meats, or alcohol; low total dietary intake of fiber, folate, fruits, or vegetables; and smoking tobacco. There have been several advances in diagnostic techniques, which, when combined with newly discovered genetic pathways, contribute to an expanding knowledge on which to base treatment. There are three known major molecular pathways of CRC carcinogenesis: the chromosomal instability pathway, the microsatellite instability pathway, and the serrated carcinoma pathway. Approximately 5% of all CRC cases will have a specific known genetic mutation associated with a well-characterized familial cancer syndrome with defined features. These syndromes are important to recognize distinctly as their identification facilitates surveillance and management with the aim of prevention, prophylaxis, and surgical cure. This review contains 2 figures, 3 tables and 50 references.  Key words: colon cancer, colorectal cancer, familial, familial adenomatous polyposis, Lynch syndrome, microsatellite, polyp, polyposis, rectal cancer, serrated

Chromosomal Aberration in Colorectal Cancer Family

2015 ◽  
Vol 15 (1) ◽  
pp. 8-11
Author(s):  
Edvins Miklasevics ◽  
Mikko Kupila ◽  
Dagnija Kalniete ◽  
Inese Eglite ◽  
Dace Berzina ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lynch Syndrome ◽  
Chromosomal Aberration ◽  
Chromosomal Aberrations ◽  
Snp Array ◽  
Hereditary Cancer Syndrome ◽  
Coding Region ◽  
Cancer Syndrome ◽  
Increased Risk ◽  
Risk Of Malignancy

Summary Introduction. Lynch syndrome, previously more commonly known as hereditary nonpolyposis colorectal cancer, is a hereditary cancer syndrome with an autosomal dominant inheritance pattern. Usually it is caused by mutations the MMR genes. In 20 - 25% of cases patients are not found to have mutations in any of these genes. Chromosomal aberrations as a cause of the Lynch syndrome were examined in this study. Aim of the study. To identify chromosomal aberrations which may lead to colorectal cancer. Material and methods. Twelve patients, corresponding to either Amsterdam I/II criteria or Bethesda guidelines, which have been tested negative for mutations in Lynch genes have been karyotyped were karyotyped with SNP array chips, in order to determine if they had potentially heritable chromosomal aberrations which could be responsible for increased risk of malignancy. Results. One patient with a 14.7Mbp duplication framed by small deletions was chosen to be the most likely patient to suffer from an inherited carcinogenic chromosomal aberration. The preceding deletion was found to contain the coding region of BRE, encoding a component of the BRCA1-A complex; we believe that this deletion is the most carcinogenic component of the aberration and likely responsible for Lynch syndrome in this case. The larger duplication furthermore contained the coding regions for 83 genes, some of which have been shown to promote malignant disease when overexpressed. Conclusion. Because of the clinically grossly tolerable nature of the aberration it is possible that it was vertically transmitted and contributed to the onset of colorectal cancer in the patient and his mother and maternal aunt.

scholarly journals High Prevalence of Hereditary Cancer Syndromes in Adolescents and Young Adults With Colorectal Cancer

2015 ◽  
Vol 33 (31) ◽  
pp. 3544-3549 ◽  
Author(s):  
Maureen E. Mork ◽  
Y. Nancy You ◽  
Jun Ying ◽  
Sarah A. Bannon ◽  
Patrick M. Lynch ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Genetic Counseling ◽  
Family History ◽  
Hereditary Cancer ◽  
Hereditary Cancer Syndrome ◽  
Hereditary Cancer Syndromes ◽  
Cancer Syndrome ◽  
History Of ◽  
Cancer Syndromes ◽  
History Of Cancer

Purpose Established guidelines recommend evaluation for hereditary cancer syndromes in patients younger than 50 years diagnosed with colorectal cancer (CRC). This group has been well described in the literature; however, patients diagnosed as adolescents and young adults are not well represented in CRC studies. Here, we define the clinical profile, including the extent of hereditary cancer syndromes and family history of cancer, in patients diagnosed with CRC at age 35 or younger. Patients and Methods We reviewed patients who underwent genetic counseling at our institution during 5 years (2009 to 2013). Data were collected regarding demographics, clinicopathologic information, tumor and genetic testing, and family history. Patients with an identified hereditary cancer syndrome were compared with those without a syndrome. Results Of the 193 patients with evaluable data, 35% had an identifiable hereditary cancer syndrome, including 23 with Lynch syndrome, 22 with mutation-negative Lynch syndrome, 16 with familial adenomatous polyposis, two with constitutional mismatch repair deficiency, two with biallelic MUTYH mutations, and one with Li-Fraumeni syndrome. Patients without a hereditary syndrome more frequently presented with metastatic disease, whereas patients with a syndrome were more likely to present at earlier stages and to have a family history of cancer. Nevertheless, a substantial proportion of the hereditary syndromes (19%) were diagnosed in individuals with no family history of the disease. Conclusion We conclude that patients diagnosed with CRC at age 35 years or younger should receive genetic counseling regardless of their family history and phenotype.

Germline multigene panel testing in colorectal cancer: Precision therapy and clinical management implications.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3582-3582
Author(s):  
Edward D. Esplin ◽  
Shan Yang ◽  
Scott T. Michalski ◽  
Daniel Esteban Pineda Alvarez ◽  
Stephen E Lincoln ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Management ◽  
Hereditary Cancer Syndrome ◽  
Cancer Genes ◽  
Cancer Syndrome ◽  
Diagnostic Laboratory ◽  
Therapeutic Implications ◽  
Panel Testing ◽  
Management Recommendations ◽  
Multigene Panel

3582 Background: Recent studies suggest that the prevalence of abnormalities in homologous recombination deficiency (HRD) genes and other cancer genes not traditionally associated with colorectal cancer (CRC) may be more common in patients with CRC than previously appreciated. Herein, we investigate the efficacy of comprehensive multigene panels in patients with CRC to identify candidates for precision therapies. Methods: DNA sequencing and exon-level copy number analysis were performed in over 9000 patients (pts) referred because of personal history of colon cancer between 2013 and 2018 at a commercial diagnostic laboratory. The genes requisitioned varied but consistently included 14 genes on a hereditary CRC panel; the patient data were de-identified and further analyzed for all 83 genes on a large hereditary cancer syndrome panel under an IRB-approved protocol. Results: Pathogenic/likely pathogenic (P/LP) findings were identified in 2101 of 9669 pts (21%), 1838 (19%) pts when MUTYH heterozygotes are excluded. When restricted to five Lynch syndrome (LS) genes, only 9% of patients had a P/LP finding, which increased to 15% of patients when 19 guidelines-based CRC genes were assessed. 137 pts (1.4%) had two or more P/LP variants. P/LP variants were in MLH1, MSH2, MSH6, PMS2, CHEK2, APC, MUTYH, BRCA2, ATM, BRCA1, PALB2, RAD50, BRIP1, TP53, EPCAM, among others, of which 1.4% were BRCA1/2. When a comprehensive multigene panel was utilized P/LP variants in genes with known therapeutic implications, such as in HRD and mismatch repair deficiency (MMRD), were detected in 1408 (14%) of patients, and 1670 (17%) had P/LP variants in genes with established clinical management guidelines. Conclusions: This study suggests that 1 in 5 patients with CRC harbor actionable germline variants, up to one-half of which remain undetected when only LS genes are tested. Comprehensive panel testing identified candidates for precision treatment and established management recommendations, and have clinical implications for both pts and their at risk family members.

scholarly journals Telomerase RNA Template Mutations Reveal Sequence-Specific Requirements for the Activation and Repression of Telomerase Action at Telomeres

2000 ◽  
Vol 20 (8) ◽  
pp. 2941-2948 ◽  
Author(s):  
John C. Prescott ◽  
Elizabeth H. Blackburn
Keyword(s):  
Enzymatic Activity ◽  
Activity Levels ◽  
Telomeric Dna ◽  
Telomere Shortening ◽  
Telomere Elongation ◽  
Telomere Binding Protein ◽  
Telomere Function ◽  
Double Base ◽  
Telomere Lengthening

ABSTRACT Telomeric DNA is maintained within a length range characteristic of an organism or cell type. Significant deviations outside this range are associated with altered telomere function. The yeast telomere-binding protein Rap1p negatively regulates telomere length. Telomere elongation is responsive to both the number of Rap1p molecules bound to a telomere and the Rap1p-centered DNA-protein complex at the extreme telomeric end. Previously, we showed that a specific trinucleotide substitution in the Saccharomyces cerevisiae telomerase gene (TLC1) RNA template abolished the enzymatic activity of telomerase, causing the same cell senescence and telomere shortening phenotypes as a complete tlc1 deletion. Here we analyze effects of six single- and double-base changes within these same three positions. All six mutant telomerases had in vitro enzymatic activity levels similar to the wild-type levels. The base changes predicted from the mutations all disrupted Rap1p binding in vitro to the corresponding duplex DNAs. However, they caused two classes of effects on telomere homeostasis: (i) rapid, RAD52-independent telomere lengthening and poor length regulation, whose severity correlated with the decrease in in vitro Rap1p binding affinity (this is consistent with loss of negative regulation of telomerase action at these telomeres; and (ii) telomere shortening that, depending on the template mutation, either established a new short telomere set length with normal cell growth or was progressive and led to cellular senescence. Hence, disrupting Rap1p binding at the telomeric terminus is not sufficient to deregulate telomere elongation. This provides further evidence that both positive and negativecis-acting regulators of telomerase act at telomeres.

Thymoma associated with malignancies may herald a hereditary cancer syndrome

2010 ◽  
Vol 9 (4) ◽  
pp. 655-657 ◽  
Author(s):  
Omid Saeed Tehrani ◽  
Emily Q. Chen ◽  
David L. Schaebler ◽  
Abdul W. Mughal
Keyword(s):  
Hereditary Cancer ◽  
Hereditary Cancer Syndrome ◽  
Cancer Syndrome
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